1. Field Of The Invention
The new 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide is a valuable intermediate product for the synthesis of cerebrally effective 4-hydroxypyrrolidin-2-on-1-yl acetamide (oxiracetam).
2. Background Art
A process is known from Pifferi et al., Il Farmaco, Ed. Sc., 1977, 32, 602, for producing the active substance. But a poor yield and expensive initial products make the process unprofitable.
BROAD DESCRIPTION OF THE INVENTION
The main object of the invention is to provide a production process which does not have such disadvantages.
This object was able to be attained in a remarkably simple way by the discovery of the new intermediate 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide. This intermediate material can be reached either from a 4-(C.sub.1 -C.sub.2)-alkoxy-3-pyrrolin-2-one or a 4-(C.sub.1 -C.sub.2)-alkoxy-3-pyrrolin-2-on-1-yl acetic acid-(C.sub.1 -C.sub.4) alkyl ester. More specifically, 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide of the formula: ##STR1## is produced by either transesterification of a 4-(C.sub.1 -C.sub.2)-alkoxy-3-pyrrolin-2-one with benzyl alcohol in the presence of an acid to 4-benzyloxy-3-pyrrolin-2-one, alkylation with 2-bromoacetic acid-(C.sub.1 -C.sub.4) alkyl ester in the presence of an alkali hyride to 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid (C.sub.1 -C.sub.4) alkyl ester and finally conversion with ammonia to the end product, or conversion of a 4-(C.sub.1 -C.sub.2) alkoxy-3-pyrrolin-2-on-1-yl acetic acid (C.sub.1 -C.sub.4) alkyl ester with benzyl alcohol in the presence of an acid to 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid benzyl ester and, optionally without its isolation, with ammonia to the end product.
Initial products with longer alkoxy or alkyl groups can easily be used. But since these groups are again split off in the course of the process, such compounds are of no significant interest.
Starting from 4-(C.sub.1 -C.sub.2)-alkoxy-3-pyrrolin2-one conversion to 4-benzyloxy-3-pyrroline-2-one is performed in a first step in the presence of an acid with benzyl alcohol. As acids for this step, sulfonic acids, such as, methane sulfonic acid or p-toluene sulfonic acid, are suitably used in catalytic amounts of suitably 0.05 to 0.2 mol. It is advantageous to operate directly in benzyl alcohol as the solvent. Benzyl alcohol is suitably used in an amount of 1.5 to 5 mol per mol of initial product.
The reaction temperature is advantageously in the range of 60.degree. to 100.degree. C. Since in this reaction a transesterification is involved, it is advantageous to perform the reaction at reduced pressure between 10 and 50 mbars to remove from the equilibrium the low-boiling alcohols that have split off.
After the completed reaction, i.e., after about 10 to 25 hours (depending on the catalyst amount of sulfonic acid), the 4-benzyloxy-3-pyrrolin-2-one can be worked up in a usual way, e.g., by azeotropic separation of the excess benzyl alcohol and optionally by crystallization of the resulting product.
in a second step the resultant product is converted with a bromoacetic acid (C.sub.1 -C.sub.4) alkyl ester in the presence of an alkali hydride to 4-benzyloxy3-pyrrolin-2-on-1-yl acetic acid-(C.sub.1 -C.sub.4) alkyl ester. Bromoacetic acid ethyl ester in an amount of suitably 1 to 1.5 mol per mol of 4-benzyloxy-3-pyrrolin-2-one is used as the preferred bromoacetic acid alkyl ester. Sodium hydride is used as the preferred alkali hydride in an amount of 1 to 1.5 mol per mol of the 4-benzyloxy-3-pyrrolin-2-one.
Advantageously, the operation is performed in a polar, aprotic solvent, such as dimethylformamide, dimethyl acetamide and acetonitrile, (especially advantageously in acetonitrile as the solvent, at a reaction temperature of 0.degree. to 40.degree. C.
The resultant 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid-(C.sub.1 -C.sub.4) alkyl ester can be converted in a last stage with ammonia to 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide. Suitably in this case the procedure is such that the initial product is advantageously dissolved in an alcohol, such as methanol or ethanol, the alcohol being previously saturated with gaseous ammonia at -10.degree. to 0.degree. C., and then the reaction mixture is stirred in an autoclave at 60.degree. to 80.degree. C. for 10 to 15 hours.
After the usual work-up, the desired intermediate product can be obtained in good yield and quality.
If the start is made from 4-(C.sub.1 -C.sub.4)-alkoxy-3-pyrrolin-2-on-1-yl acetic acid (C.sub.1 -C.sub.4) alkyl ester, a conversion is performed in a first step with benzyl alcohol, in an acid manner to 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid benzyl ester. As acids for this step, suitably sulfonic acids, preferably methane sulfonic acid or p-toluene sulfonic acid, in catalytic amounts of suitably 0.05 to 0.2 mol are used.
It is advantageous to work directly in benzyl alcohol as the solvent. The benzyl alcohol is suitably used in an amount of 2.5 to 5.0 mol per mole of initial product. The reaction temperature is advantageously in the range of 80.degree. to 120.degree. C. As in the production of 4-benzyloxy-3-pyrrolin-2-one, it is advantageous to perform the reaction at reduced pressure, preferably between 10 to 50 mbars.
After reaction is completed, i.e., after about 7 to 10 hours, 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid benzyl ester can be obtained after the usual work-up and optionally by purification by means of recrystallization.
In a last step, conversion with ammonia to the desired intermediate product to 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide can then be performed. Advantageously the alcohol, preferably methanol and ethanol, functioning as solvent for this purpose is saturated with gaseous ammonia at -10.degree. to 0.degree. C., then the 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid benzyl ester is added and finally the reaction mixture is stirred in the autoclave at 60.degree. to 80.degree. C. for 6 to 10 hours.
After a simple work-up, the desired intermediate product can be obtained in good yield and quality.
The 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide can be used as an especially advantageous intermediate product for production of cerebrally effective 4-hydroxypyrrolidin-2-on-1-yl acetamide.
Suitably for this purpose catalytic hydrogenation is performed in a first step.
Noble metal catalysts are suitably used as catalysts, which causes a selective debenzylation. Preferably palladium, applied to a usual support material, preferably on activated carbon, with a catalyst content of 1 to 10 percent is used. The catalyst amount suitably ranges between 5 and 10 percent by weight, in relation to the amount of 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide used.
The intermediately resultant 2,4-dioxopyrrolidin-1-yl acetamide can be reduced with complex borohydrides, preferably with alkali borohydrides, especially preferably with sodium borohydride, to the end product. Thus, it is advantageous to perform the debenzylation in a polar aprotic solution, such as, dimethylformamide or dimethyl acetamide, under a pressure of suitably 1 to 20 bars and at a temperature suitably between 0.degree. and 30.degree. C. The alkali borohydride is preferably used in an amount of 0.5 to 0.8 mol per mol of 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide.
While maintaining the polar aprotic solvent, the operation is suitably performed at a temperature of 0.degree. to 30.degree. C. In this way, a corresponding advantage of the process described here applies, because the sensitive 2,4-dioxopyrrolidin-1-yl acetamide tending to dimerization is kept in solution and must not be isolated, whichever, is possible.
If catalytic hydrogenation is selected for conversion of the intermediate 2,4-dioxopyrrolidin-1-yl acetamide to the end product, advantageously the operation for the catalytic hydrogenolysis is performed in a polar protic anhydrous solvent, such as, methanol, ethanol or acetic acid, at suitably 1 to 20 bars and a temperature of suitably 0.degree. to 30.degree. C. The catalyst and catalyst amount advantageously remain unchanged with respect to the catalytic hydrogenolysis in polar aprotic solvents.
The catalytic hydrogenation is then suitably performed with platinum catalysts, such as platinum oxide or platinum, applied in an amount of 1 to 10 percent to a support, preferably to activated carbon.
The catalyst amount suitably ranges between 1 and 10 percent by weight in relation to the 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide. The hydrogen pressure suitably is between 5 to 20 bars, the temperature is between 0.degree. and 30.degree. C. Also in this catalytic reduction it is advantageous to keep the intermediately formed 2,4-dioxopyrrolidin-1-yl acetamide in solution and not to isolate it.
It is especially preferable to perform the debenzylation of the 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide by catalytic hydrogenolysis and the catalytic reduction by hydrogenation of the intermediate 2,4-dioxopyrrolidin-1-yl acetamide with hydrogen as a one-pot process with palladium/platinum mixed catalysts. Again the polar aprotic anhydrous solvents, such as, methanol, ethanol or anhydrous acetic acid, are suitably used. The hydrogen pressure ranges advantageously between 5 and 20 bars and the temperature between 0.degree. and 30.degree. C. Suitably a palladium/platinum mixed catalyst is used, whose palladium to platinum ratio is 5 to 1 to 1 to 2. The palladium portion is preferably used in an amount of 1 to 10 percent, applied to a usual support, preferably to activated carbon. The platinum portion can be present as platinum oxide or also as platinum, applied in an amount of 1 to 10 percent to a usual support, preferably to activated carbon. The mixed catalyst is used in an amount of suitably 5 to 15 percent by weight, in relation to the 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide.
The work-up of the end product, independently of which process is selected, can take place in a usual process manner. The resultant 4-hydroxypyrrolidin-2-on-1-yl acetamide can optionally be purified by recrystallization.
Via the new 4-benxyloxy-3-pyrrolin-2-on-1-yl acetamide as a new intermediate product and with the help of the process according to the invention, one can in the described way produce 4-hydroxy-3-pyrrolidin2-on-1-yl acetamide in good yields and in purities greater than 98 percent.